This invention pertains to a sustained release complex, Compound (I), which comprises Compound (A), having the formula
or a pharmaceutically acceptable salt thereof, and a copolymer comprising poly-(I)-lactic-glycolic-tartaric acid (P(I)LGT), wherein the amino group of said Compound (A) is ionically bound to a carboxyl group of the P(I)LGT. The present invention further pertains to a process for making said sustained release complex. Further still, the present invention is directed to a pharmaceutical composition comprising said sustained release complex and a pharmaceutically acceptable carrier(s).
Further, since Compound (A) is an analogue of somatostatin and it is well known to those skilled in the art that the known and potential uses of somatostatin are varied and multitudinous, this invention is also directed to the use of Compound (A), Compound (I) or microparticles of Compound (I) to treat a disease or condition in a patient in need thereof, which comprises administering Compound (A), Compound (I) or microparticles of Compound (I) to said patient, wherein the diseases or conditions to be treated are selected from the group consisting of gastroenterological conditions and/or diseases, such as Crohn's disease, systemic sclerosis, external and internal pancreatic pseudocysts and ascites, VIPoma, nesidoblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, diarrhea, AIDS related diarrhea, chemotherapy related diarrhea, scleroderma, Irritable Bowel Syndrome, pancreatitis, upper gastrointestinal bleeding, postprandial portal venous hypertension especially in cirrhotic patients, complications of portal hypertension, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux and in treating endocrinological diseases and/or conditions, such as Cushing's Syndrome, gonadotropinoma, hyperparathyroidism, Graves' Disease, diabetic neuropathy, macular degeneration, hypercalcemia of malignancy, Paget's disease, and polycystic ovary disease; in treating various types of cancer such as thyroid cancer, leukemia, meningioma and conditions associated with cancer such as cancer cachexia; in the treatment of such conditions as hypotension such as orthostatic hypotension and postprandial hypotension and panic attacks.
Many drug delivery systems have been developed, tested and utilized for the controlled in vivo release of pharmaceutical compositions. For example, polyesters such as poly(DL-lactic acid), poly(glycolic acid), poly(ε-caprolactone) and various other copolymers have been used to release biologically active molecules such as progesterone; these have been in the form of microcapsules, films or rods (M. Chasin and R. Langer, editors, Biodegradable Polymers as Drug Delivery Systems, Dekker, NY 1990). Upon implantation of the polymer/therapeutic agent composition, for example, subcutaneously or intramuscularly, the therapeutic agent is released over a specific period of time. Such bio-compatible biodegradable polymeric systems are designed to permit the entrapped therapeutic agent to diffuse from the polymer matrix. Upon release of the therapeutic agent, the polymer is degraded in vivo, obviating surgical removal of the implant. Although the factors that contribute to polymer degradation are not well understood, it is believed that such degradation for polyesters may be regulated by the accessibility of ester linkages to non-enzymatic autocatalytic hydrolysis of the polymeric components.
Several EPO publications and U.S. Patents have addressed issues of polymer matrix design and its role in regulating the rate and extent of release of therapeutic agents in vivo.
For example, Deluca (EPO Publication 0 467 389 A2) describes a physical interaction between a hydrophobic biodegradable polymer and a protein or polypeptide. The composition formed was a mixture of a therapeutic agent and a hydrophobic polymer that sustained its diffusional release from the matrix after introduction into a subject.
Hutchinson (U.S. Pat. No. 4,767,628) controlled the release of a therapeutic agent by uniform dispersion in a polymeric device. It is disclosed that this formulation provides for controlled continuous release by the overlap of two phases: first, a diffusion-dependent leaching of the drug from the surface of the formulation; and second, releasing by aqueous channels induced by degradation of the polymer.
PCT publication WO 93/24150 discloses a sustained release formulation comprising a peptide having a basic group and a carboxy-terminated polyester.
U.S. Pat. No. 5,612,052 describes cation-exchanging microparticles made typically of carboxyl-bearing polyester chains onto which basic bioactive agents are immobilized to provide a control release system within an absorbable gel-forming liquid polyester.
Compound (A) is described and claimed in U.S. Pat. No. 5,552,520, which is assigned to the assignee hereof.
PCT publication WO 97/40085, assigned to the assignee hereof, discloses biodegradable polyesters comprising lactic acid units, glycolic acid units and hydroxy-polycarboxylic acid units such as tartaric acid or pamoic acid and processes for making said polyesters. More specifically, it discloses poly-lactide-glycolide-tartaric acid polymers in the ratio 65/33/2, respectively.
PCT publication WO 94/15587, assigned to the assignee hereof, discloses ionic conjugates of polyesters having free COOH groups with a bioactive peptide having at least one effective ionogenic amine. More specifically, it discloses that the polymers are made polycarboxylic by reacting the co-polymers with malic acid or citric acid. U.S. Pat. No. 5,672,659, is the U.S. national phase continuation application of WO 94/15587. U.S. Pat. No. 5,863,985 is a continuation of U.S. Pat. No. 5,672,659. Pending U.S. application Ser. No. 09/237,405 is a CIP of U.S. Pat. No. 5,863,985, which additionally discloses a polyester which must include citric acid, ε-caprolactone and glycolide; compositions comprising the immediately foregoing polyesters and a polypeptide; a polyester that must include tartaric acid as one of its members; compositions comprising the immediately foregoing polyester and a polypeptide; and the foregoing compositions in the shape of rods which are optionally coated with a biodegradable polymer.
PCT publication WO 97/39738, assigned to the assignee hereof, discloses a method of making microparticles of a sustained release ionic conjugate as described in WO 94/15587.
The contents of the foregoing patents, applications and publications are incorporated herein in their entirety.
The present invention is directed to a preferred embodiment of a sustained release ionic conjugate of polymer poly-lactide-glycolide-tartaric acid and Compound (A), also known as Compound (I), which is characterized by the surprising and non-obvious property of zero-order release of Compound (A) from the conjugate. More preferably, the ionic conjugate, Compound (I), is in the form of microparticles.